DESCRIPTION: (Applicant's Abstract) Results from two recent studies have led to the proposal that fenfluramine, when given in combination with phentermine, is effective in the treatment of drug abuse. While double-blind, placebo-controlled studies validating this proposal are not yet available, efforts to carry out such studies are underway. Since successful development of any pharmacologic drug abuse treatment strategy will require information on both treatment safety and efficacy, the present studies are designed to assess the safety of fenfluramine/phentermine treatment. Safety concerns arise because there is a large body of preclinical data (including data in nonhuman primates) which strongly suggests that fenfluramine produces toxic effects on serotonin neurons in the central nervous system. While the serotonin neurotoxic potential of fenfluramine (alone or in combination with phentermine) is well documented in animals, its long-term effects in humans have not been investigated, largely because of the difficulty inherent in assessing serotonin neuronal integrity in the living human brain. Positron emission tomography (PET), when used in conjunction with neuron specific ligands, is an imaging technique that can now be used to study central serotonin neurons in humans during life. The present studies will therefore use PET imaging with the serotonin transporter ligand [11C]McN-5652, in conjunction with studies of CSF 5-HIAA, and serotonin-linked functions and behaviors, to assess the neurobiological effects of pharmacotherapy with fenfluramine and phentermine upon the structure and/or function of serotonin neurons in the living human brain. In this prospective, double-blind, placebo-controlled study, the following treatment groups will be used: 1) Fenfluramine/phentermine; 2) Fenfluramine alone; 3) Phentermine alone; 4) Placebo control; (n=15/group). Since the study cohort will consist of subjects undergoing treatment of obesity (where fenfluramine/phentermine is indicated and has efficacy), an additional control group will be incorporated (non-obese control group) to guard for possible effects of obesity per SE on serotonin measures. Subjects in all groups will undergo PET, CSF, neuroendocrine and functional studies of 5-HT-linked behaviors before and after treatment. Studies after treatment will be performed 4-8 weeks after completion of treatment, so as to measure long-rather short-term effects of treatment of serotonin neural indexes. The project's long-term goals are: 1) To better define the risks of fenfluramine/phentermine treatment in humans; and 2) To use obesity as a model for analyzing the risk/benefit ratio for fenfluramine and phentermine in the treatment of drug abuse.